Alkoxxethylguanameses



Unit St em ALKOXYETHYLGUANAMINES .1 Seymour L. Shapiro, on Hudson, man,Bronxville, and Vincent A. Parr-i110, Itayside, N.Y.

No Drawing. Application November 26, 1 958,. Serial No. 776,415 I alClaim. (Cl. 260-4498) This invention concerned with novel triazinecompounds which havevaluable physiologieal'proper'ties'. ,Moreparticularly, this invention is concerned'with tnazine compounds of thefollowing formulae 1 01110115011, v t V ta Ba l ' CHiCHr-ORi N l inwherein R1 is methyl and" ethyl, R is selected from the group consistingof o-methyl and rn-methyl, rn-chloro and p-chloro, and R is selectedfrom the group consisting of hydrogen, o-methyl, m-methyl, m-chloro andp-chloro. The compounds are substituted guanamines and specifically, are'2-amino-4-(substituted anilino)-,6- (B-alkoxyethyl) -s-triazines.

"1 2,937,172 gate med May 17, 1960 I LDmtn. is the minimum lethal doseas established by subcutaneous injection in mice. b A0 represents theanticonvulsant ratln and the method for evaluation is recorded byShapiro et 111., J. Am. hem. Soc., 80, 1648 (1958 The followingstructural modifications such as replacemen't ofv the substitutedanilino group with alkyl or arylalkyl-amino groups, or having thehydrogen or the ethyl group on'the anilino nitrogen replaced by methylor bulkier groups such as allyl, butyl or isoamyl, or having anunsubstituted anilino group, or fiuoro or iqdosubstituted 'aniliriovgroups, or p-toluidino groups, were asso- The compounds of thisinvention have anticonvulsant,

hypnotic and sedative properties.

The synthesis of the compounds ofthis invention proceed by' interactionof the B-alkoxypropionate ester with the biguanide inanalcoholic-solverit. Catalytic quantiv} ties of sodium methoiiide maybe added. After a'suitable reaction period, usually from 24-96 hours at20 C., the reaction mixture is decanted into water and the productrecovered by filtration. Alternatively, the biguanide is treated inaqueous acetonitrile with the p-alkoxy acid chloride, using sodiumhydroxide as an acid acceptor to yield the product.

The required biguanides which serve as initial reactants are prepared byreaction of equivalent quantities of the substituted aniline, and 3 Nhydrochloric acid and dicyandiamide.

The compounds listed in Table I are indicative of the scope of theinvention, and the pharmacological activity of the compounds.

TABLE I Characteristics and anticonvulsant activity of typical triazinesCHICHT'ORI ciated with considerable reduction or disappearance of theanticonvulsant activity.

The compounds of this invention are weak bases, and will form-salts withthe strong mineral acidsnsuch as hydrochloric, hyd'robromic, sulfuricacid and the like, and such'sal-ts-are within the purview of thisinvention.

The present invention will be described in greater detail in conjunctionwith. the following specific examples which are typicalbut are not to beconstrued as limiting.

" EXAMPLE 1 2-amin0-4-(o-mcthylanilino) 6 4 (B-methoxyethyD-striazine-Asolution of 5.0 g. (0.022 mole) of (o-methylphehyDbiguanid hydrochloridein ml.- of methanol "'w'as'trea'ted with-a solution of 1.02 g. (0.044mole) of sodium in 30 ml. of methanol followed by 3.5 ml. ofmethylUS-methoxy)propionate. After 72 hours at 20 C. the reactionmixture was decanted into ml. of water and after 7 days the product, 2.5g., which separatedwas recrystallized (acetonitrile) and melted at121-124 C.

Analysis.Calcd. for C H N O: C, 60.2; H, 6.6. Found: C, 60.6; H, 7.2.'

EXAMPLE 2 EXAMPLE 3 2-amino-4-(p-chloroanilino) 6(fi-methoxyethyD-striazine.In a manner similar to that described forExample 1, and using (p-chlorophenyl)biguanide, the product (1.3 g.) wasobtained in a 0.01 mole run, was recrystallized (methanol-water) andmelted at -133 C.

Analysis.-Oalcd. for C H ClN O: C, 51.5; H, 5.0; N, 25.0. Found: C,52.3;1-1, 5.1; N, 25.4.

mauve EXAMPLE 4 Z-amino-4-(m-methylanilino) 6(fi-methoxyethyD-szriazine.-In a manner similar to that described forExample 1, and using (m-methylphenyl)biguanide, the product (2.1 g.) wasobtained in a 0.03 mole run, was recrystallized (acetonitrile) andmelted at 111-112 C.

Analysis.-Calcd. for C H N O: C, 60.2; H, 6.6; N, 27.0. Found: C, 60.3;H, 6.6; N, 27.2.

EXAMPLE 5 2 amino-4-(N-ethyl-[o-methyl] anilin0)-6-(B-meth0xyethyl)-s-triazine.eA suspension of 6.8 g. (0.031 mole) ofN'-ethy1-N'-(o-methylphenyl)biguanide hydrochloride in 25 ml. ofacetonitrile and a solution of 2.5 g. (0.062 mole) of sodium hydroxidein 16 ml. of water was stirred and maintained at 0 C. by externalcooling during the addition of a solution of 6.3 g. (0.046 mole) ofB-methoxypropionyl chloride in ml. of acetonitrile. The reaction mixturewas stored at 20 C. for 4 hours and the solvents evaporated undervacuum. The residue was treated with 50 ml. of methanol and decantedinto 125 ml. of water. The precipitate of product (7.1 g.) whichseparated was recrystallized (acetonitrile) and melted at 105-106 C.

Analysis.-Calcd. for CH21N50: C, H, N, 24.4. Found: C, 62.9; H, 7.3; N,24.4.

EXAMPLE 6 ethyl)-s-triazine.-In a mannersimilar to that described inExample 1, and using N'-ethyl-N-(p-chlorophenyl) biguanidehydrochloride, the product (3.1 g.) obtained in an 0.018 mole run wasrecrystallized (acetonitrile) and melted at 107112 C.

AIZHIYSiSr-CfilCd. fOI' C14H1BCIN5OIVC, H, 5.9; N, 22.7. Found: C, 55.1;H, 5.8; N, 22.8.

EXAMPLE 7 E AM E 8 2-amino-4-(m-methylanilino) 6 (p gthoxyethyb-striazine.-Asolution of 5.0 g. (0.022 mole) of (In-methylpheny1)biguanidehydrochloride in 50 ml. of methanol was treated with a solution of 1.02g (0.044 mole) of sodium in 28 ml. of methanol followed by 3.5 ml. ofethyl (B-ethoxy)propionate. After 72 hours at 20 C. the reaction mixturewas decanted into 90 m1. of water. After 7 days, the product (2.7 g.)which separated was recrystallized (acetonitrile) and melted at 1491S1C.

Analysis.-.-Ca1cd. fOI' C14H19N5OZ C, H, 7.0- Found: C, 61.6; H, 6.6.

EXAMPLE 9 2-amin0-4-(N-ethylanilina) 6 a p ethoxyethyl-s-triazine.In amanner similar to that described for Example 8, usingN-ethyl-N'-phenylbiguanide hydrochloride, the product (3.5 g.)'w'asobtained and recrystallized (acetonitrile) and melted at -82 C.

Analysis.Calcd. for C H N O: C, 62.7; H, 7.4. oun C. .3- V r h novelcmpq nds o his n nt n c n b ia d t so id o i id Ph rma eu i a carriers aformulated into the form of tablets, powder packets or capsules, or,dissolved in suitable solvents for oral and parenteral administrationfor human or veterinary use.

It is to be understood that it is intended to cover all changes andmodifications 'of the examples of the invention herein chosen for thepurpose of illustration which do not constitute departure from thespirit and scope of the invention.

We claim:

The compound OHIOHQOCH! References Cited in the file of this patentUNITED STATES PATENTS 2,309,663 Oldham Feb. 2, 1943 2,394,526 ThurstonFeb. 4, 1946 2,777,848 Schae fer Jan. 15, 1957 2,926,165 Shapiro et alFeb. 23, 19.60

